Functional Dyspepsia

Michael Fried Division of Gastroenterology and Hepatology

University Hospital Zurich, Switzerland

Dyspepsia

Functional Dyspepsia

Non-GI Causes (cardiac disease,

muscular pain, etc.)

Structural Dyspepsia (GERD, PUD, pancreatic disease, gallstones, etc.)

Diagnostic Criteria* for Functional Dyspepsia

Rome III

* Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.

Must include one or more of the following:

and no evidence of structural disease (including upper endoscopy) to explain the symptoms

Bothersome postprandial

fullness

Early satiation

Epigastric pain

Epigastric burning or or or

Tack J et al, Gastroenterology, 2006;130:14661479

Pathophysiology ?

Carbone F and Tack J. Dig Dis 2014, 32: 222-229

Futagami S et al. Aliment Pharmacol Ther 2015; 41: 177-188

Postinfectious FD and IBS

VorfhrenderPrsentationsnotizenMetaanalysis of six studies that demonstrated relative risk for postinfectious FD and postinfectious IBS. The relative risk and its confidence intervals (95% CI) for each study are plotted on a logarithmic sacle. The diamondshaped box represents the pooled relative risk and the 95% CI.

Do subtypes make sense?

27% non-specific

31% overlapping

Talley et al. 2001. J Clin Gastroenterol Talley et al. Gastroenterology 1993

Bytzer et al. Scand J Gastroenterology 1992

Lack of discriminant value of dyspepsia subgroups

VorfhrenderPrsentationsnotizensteht so in Rome IIist eine schne Terminologieklinisch aber bedeutungslos, denn berlappung und unspezifisch !!!hilft nicht, organische ursachen der Dyspepsie zu erkennen: 52. Bytzer P, Schaffalitzky de Muckadell O. Prediction of majorpathological conditions in dyspeptic patients referred for endoscopy.A prospective validation study of a scoring system. ScandJ Gastroenterol 1992;27:987992.Talley NJ, Weaver AL, Tesmer DL, Zinsmeister AR. Lack ofdiscriminant value of dyspepsia subgroups in patients referredfor upper endoscopy. Gastroenterology 1993;105:13781386.

Camillieri glaubt das nicht

Dyspepsia: a symptom complex

< 0.1% 1 symptom; 99% >2 symptoms; > 80% >5

Tack J et al, Gastroenterology, 2006;130:14661479

Ford AC et al. Clin Gastroenterol Hepatol. 2010; 8: 830-837

Meta-analysis, 151 papers included, N= 5389 patients

Broad definition of dyspepsia

Rome 3 criteria for dyspepsia

VorfhrenderPrsentationsnotizen(A) Pooled prevalence of various endoscopic findings in studies using a broad definition of dyspepsia. (B) Pooled prevalence of various endoscopic findings in studies using the Rome criteria to define dyspepsia.

DD

Main differential diagnoses for dyspepsia 1. Peptic ulcer (chronic) 2. GERD (w/wo esophagitis) 3. Malignant disease 4. Functional dyspepsia

Diagnosis after exclusion

AGA Technical Review on the Evaluation of Functional Dyspepsia. Gastroenterology 2005

VorfhrenderPrsentationsnotizen4 major causes

Organic causes of dyspeptic symptoms

Peptic clcer disease GERD Medications (ASA/NSAIDS, Abx) Gastroparesis Gastric neoplasm Cholelithiasis, choledocholithiasis Pancreatitis (acute or chronic) Carbohydrate malabsorption Ischemic bowel disease Other GI malignancy (ep. Pancreatic cancer) Systemic disease (DM, Thyroid, Parathyroid, CTD) Intestinal parasites

Medications and dyspepsia

NSAR cause dyspepsia in up to 20% of the patients (including COX-2 inhibitors)

COX-2 inhibitor consumation decreases, but low dose aspirin use increases

Identify: - Alendronat - Acarbose - Metformin - Orlistat - Digitalis - Theophylline - Potassium - Antibiotics (Erythromycin)

Hawkey et al. Gut 2003

Bytzer et Hallas. Aliment Pharmacol Ther 2000 Ofman et al. Arthritis Rheum 2003

VorfhrenderPrsentationsnotizenKeine etablierten Daten zu dyspsie-induktion ausser bei NSAIDs

Overland MK. Med Clin N Am; 2014; 98: 549-564

Etiology of dyspepsic symptoms ?

Alarm symptoms and signs History Weight loss

Dysphagia

Recurrent vomiting

Icterus

FA: Ca / Celiac d.

Onset > 45 yrs

Signs

Fever

Pathological status

GI bleeding signs

Lab

Anemia, Fe-deficiency

Leukocytosis

CRP

Wallace MB et al. Gut 2001; 49: 29-34

Age > 45 or any alarm symptom as predictor of major endoscopic findings

Canadian trial (7004 pts

Abdominal sonography ?

explains only rarely patients symptoms

therapeutic gain only 1-3%

- exclusion of pancreas pathology

- gallbladder stones mostly incidental

not recommended in patients < 45 years

AGA Technical Review: Gastroenterology 2005; 129:1756-80

DGVS-Leitlinien Z Gastroenterol 2001; 39:937-956

General therapeutic measures in FD ?

Explanation of benign nature of disease ("re-assurance")

Good patient-doctor relationship

Dietary counceling (diet assessment, more meals, smaller portions, less fat, avoidance of nutrients which induce symptoms)

Healthy life style

Talley et al. Am J Gastroenterol 2005 Lacy et al. AP&T 2012

Functional dyspepsia always PPI ?

41 % (PPI) vs. 32 % (placebo) RR- reduction 10 % (95% CI, 2.7% 17.3%) NNT 14

Wang WH et al. Clin Gastroenterol Hepatol 2007;5:178-85

Favors PPI Favors plac.

Metaanalysis (2007), 3725 patients

PPI effective in patients with EPS and refluxlike symptoms, less effective in patients with PDS-type dyspepsia Lower dose equivalent to standard dose (e.g.: 10 mg vs. 20 mg omeprazole)

PPI Basic therapy Effect independent of dose More effective in EPS with refluxlike symptoms

Newer data

Japan: PPI monotherapy better than H2-RA + prokinetic for PDS China: PPI more effective for treatment of epigastric burning than

pain, postprandial fullness, early satiety

Sakaguchi et al. World J Gastroenterol. 2012; 18: 1517-24 Xiao et al. Am J Gastroenterol 2010;105: 2026-31

VorfhrenderPrsentationsnotizenJapanese trial: 114 Patienten mit Rabeprazol 10mg 1x/Tag versus Famotidine 10mg BID plus Mosapride 5mg TID fr 4 Wochen

Symptom improvement after HP -Eradication?

metaanalysis (Cochrane database) 2006, 21 RCT / 3566 pts.

H. pylori eradication has a small (but significant) effect in H.pylori positive functional dyspepsia

NNT = 15

Suzuki et al, J Neurogastroenterol Motil 2011; 17 Moayyedi P et al. Cochrane Database Syst Rev 2006

Antidepressants for functional dyspepsia ?

12 heterogenous small studies: relative risk reduction 45% vs placebo

2/4 studies with levosulpiride

Hojo M et al. J Gastroenterol 2005;40:1036-42

Antidepressants

Amitryptiline (Saroten; 3x10mg/d) Japanese RCT, 27 FD patients with no response to H2-RA/prokinetics

Otaka M et al. APT 2006; 21S:42-46

Hypnotherapy ?

Calvert EL et al. Gastroenterol 2002;123:1778-85

126 patients randomized to hypnotherapy (3 not completed) supportive therapy (13 not completed) conventional treatment (10 not completed)

Functional dyspepsia prokinetics ?

Hiyama T et al. J Gastroenterol Hepatol 2007;22: 304-10

Metaanalysis 2007, 27 studies: relative risk reduction (symptom free): 33% with prokinetic vs. plac NNT=6 BUT: no longterm data 21/27 studies with cisapride (unavailable) domperidon (Motilium) and metoclopramide (Paspertin): less

effective than cisapride

Veldhuyzen, van Zanten, Am J Gastroenterol 2001; 96: 689-696

Prokinetics: Levosulpiride (Dogmatil)

Mearin F et al. Clin Gastroenterol Hepatol 2004.2: 301-308 Corazza GR, Biagi F, Albano O, et al. It J Gastroenterol 1996; 28: 317-323

Mansi C et al. Aliment Pharmacol Ther. 2000;14:56156-9

Action peripheral and central D2-receptor antagonist, partial ENS 5-HT4

agonist Effects more potent than domperidone, metoclopramide and cisparide to

reduce FD symptoms similar efficacy to accelerate gastric emptying as cisapride

Dose 3x25mg - 3x50mg/d (Sanofi-Aventis, 50mg capsules) Side effects gastrointestinal, tachykardia, prolactin elevation

VorfhrenderPrsentationsnotizenSulpirid Stada 50mg 100 Tabletten 18.5 Euro (Tagespreis 25 Cent (30 Rappen)

Lacy BE et al. Aliment Pharmacol Ther. 2012; 36: 3-15

VorfhrenderPrsentationsnotizenProposed treatment algorithm for FD. In this algorithm the patient with dyspepsia undergoes an upper endoscopy which, by definition, has to be grossly normal. If biopsies for Helicobacter pylori (HP) were performed and were negative (upper left corner) then the patient should be treated with a daily proton pump inhibitor (PPI). If symptoms (Sx) do not improve after 48 weeks, a therapeutic trial with a TCA should be initiated (the percentage of patients with FD symptom resolution is shown in parentheses). If upper endoscopy is grossly normal but gastric biopsies were not obtained for H. pylori, then the algorithm should begin with an assessment of H. pylori prevalence (upper right side). If present, H. pylori should be treated and the occasional patient with H. pylori will experience FD symptom resolution. If the patient is H. pylori-negative, then PPI therapy should be initiated (upper middle of diagram). The percentage of H. pylori-negative FD patients previously treated with a PPI and then a TCA, who will improve with an anti-nociceptive agent or CAM, is unknown. Therapeutic Gain (T.G.) refers to the reported symptom improvement rate above the placebo response (i.e. not including the placebo response). The overall Response Rate (R. R.) refers to the overall response rate which includes the placebo response. For example, on the right hand side of the diagram, the therapeutic gain (T.G.) of treating an FD patient who is H.P (+) has been reported as 614%. Alternatively, this portion of the figure could have been labelled using the overall response rate (R.R.) for FD symptom improvement in a patient treated for HP, which is approximately 3139%, as this includes the placebo response rate which is approximately 25%.

Zala A et al. Expert Opin Emerging Drugs 2015; 20:221-233

FD: disturbed motility, sensitivity, inflammation, brain factors GI infections are risk factors for FD Low predictive value of FD symptoms for a positive diagnosis Alarm symptoms do not reliably predict organic disease Patients with FD should at least have once a gastroscopy;

value of ultrasound is uncertain PPIs are basic FD therapy, independent if patients present

reflux-like symptoms or not HP eradication is effective in a small subgroup Some (amitryptiline) antidepressants are effective to treat FD Hypnotherapy has a long-term effect on FD symptoms Prokinetics (sulpiride; acotiamide) should be tried if PPI, HP

eradication and antidepressants have failed

Take home messages

Pierre-Auguste Renoir. Le djeuner des canotiers

Functional DyspepsiaDyspepsiaFoliennummer 3Pathophysiology ?Postinfectious FD and IBSFoliennummer 7Dyspepsia: a symptom complexFoliennummer 9DDOrganic causes of dyspeptic symptomsMedications and dyspepsiaFoliennummer 13Alarm symptoms and signsFoliennummer 15To scope or not?Benefit of upper gi endoscopyFoliennummer 17General therapeutic measures in FD ?Functional dyspepsia always PPI ?PPISymptom improvement after HP -Eradication?Antidepressants for functional dyspepsia ?AntidepressantsHypnotherapy ?Functional dyspepsia prokinetics ? Prokinetics: Levosulpiride (Dogmatil)Foliennummer 27Foliennummer 28Foliennummer 29Foliennummer 30